Development of a broadly cross-protective capsular group B meningococcal (MenB) vaccine has been hampered by poor capsular immunogenicity and often diverse and poorly cross-protective subcapsular antigens. The MenB MC58 strain genome has facilitated the discovery of novel, relatively conserved vaccine candidates. The four-component MenB (4CMenB) investigational vaccine contains factor H-binding protein (fHbp; variant 1), neisserial heparin-binding antigen (NHBA), Neisserial adhesin A (NadA) and PorA P1.4-containing outer membrane vesicles. The latter are known to elicit protection against homologous strains. Clinical trials have demonstrated protective responses in infants and adults against isolates expressing homologous PorA or fHbp (subvariant 1.P1), or heterologous NadA (variant 2). Cross-protective responses have also been demonstrated in adults and, to a lesser extent, infants, against isolates expressing heterologous fHbp variant 1 subvariants. The contribution of NHBA is still poorly understood. MenB currently accounts for 87% of invasive meningococcal disease in England and Wales. The proportion of disease due to the ST-269 clonal complex (cc269) peaked at 45.6% in 2006 and is currently approximately 24.2%. The aims of this study were (i) to genotypically assess potential 4CMenB coverage against recent English and Welsh invasive disease isolates and, specifically, cc269 isolates from England and Wales and other countries, (ii) to compare phenotypic expression levels of the 4CMenB antigens (excluding PorA) among typical cc269 isolates, and (iii) to assess 4CMenB responses against typical cc269 isolates among healthy adults administered 4CMenB.Full length alleles for fHbp variant 1, NHBA and NadA variants 1, 2 and 3 were present in 64.6%, >99% and 7.1%, respectively, of English and Welsh invasive disease isolates from 2007/8. Between 67.5% and >99% (adults) or 25.7% and 43.5% (infants) of the isolates were predicted to be covered by 4CMenB. cc269 comprised two antigenically distinct lineages (clusters) centred around ST-269 and ST-275, respectively. These accounted for 57% and 40% of cc269 in 2007/8. Both clusters effectively lacked nadA and PorA P1.4. The predominant fHbp;NHBA profiles represented by the respective clusters were 1.P15;P0021 and (1.P13 or 2.P19);P0017. Between 77.4% and 100% (adults) or 2.2% and 27.1% (infants) of cc269 isolates from 2007/8 were predicted to be covered by 4CMenB. Estimates for infants were conservative due to e.g. the exclusion of NHBA. Serum bactericidal antibody (SBA) analyses targeting typical fHbp variant 1-expressing cc269 strains, indicated high levels of coverage among adults administered 4CMenB. Notable differences among genotypically matched isolates e.g. in terms of SBA geometric mean titres, were not reflected in the relative fHbp and NHBA expression levels. Such differences may lead to conflicting estimates of coverage in infant populations. Whilst these are investigated further it seems prudent to use typical isolates giving mid-range responses when assessing SBA, and therefore protection, among infants. Potential 4CMenB coverage of cc269 and the broader meningococcal population in England and Wales was high among adults and encouraging among infants when compared to that of existing MenB vaccines.